Imidazo[1, 2-a] pyrazines for the treatment of irritable bowel syndrome

ABSTRACT

Provided herein are methods for treating a subject afflicted with irritable bowel syndrome comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition that comprises a pharmaceutically acceptable carrier and a compound of the formula  
                 
 
     wherein:  
     X is CHR 5 , NR 5 , O, S, S(O) n  or a single bond, wherein n is equal to 0, 1 or 2;  
     D is aryl or heteroaryl attached through an unsaturated carbon atom and wherein said aryl or heteroaryl is optionally substituted at any available position with from 1-5 of A 1 , A 2 , A 3 , A 4  and A 5 ; and  
     R 2  is C 1-4  alkyl or C 3-8  cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C 1-4  alkoxy, or wherein when X is a bond, R 2  is CN, CF 3 , or C 2 F 5 .

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of co-pending U.S. application Ser. No. 09/905,097, filed Jul. 13, 2001, now allowed, which in turn claims priority of provisional application Serial No. 60/218,339. These priority applications are hereby incorporated herein in their entireties.

FIELD OF THE INVENTION

[0002] This invention relates to compounds which are novel imidazo[1,2-a]pyrazines, and to the use of such compounds as CRF receptor antagonists in the treatment of various neurological disorders.

BACKGROUND OF THE INVENTION

[0003] Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

[0004] Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

[0005] In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)].

[0006] Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

[0007] It has also been postulated that CRF has a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].

[0008] Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone-in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

[0009] It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.

[0010] The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

[0011] The following publications each describe CRF antagonist compounds; however, none disclose the compounds provided herein: WO95/10506; WO99/51608; WO97/35539; WO99/01439; WO97/44308; WO97/35846; WO98/03510; WO99/11643; PCT/US99/18707; WO99/01454; and, WO00/01675.

SUMMARY OF THE INVENTION

[0012] This invention provides a compound of the formula (I):

[0013] wherein: X is CHR⁵, NR⁵, O, S, S(O)_(n) or a single bond, wherein n is equal to 0, 1 or 2; D is aryl or heteroaryl attached through an unsaturated carbon atom and wherein said aryl or heteroaryl is optionally substituted with from 1-5 A¹-A⁵; R¹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, NR⁶R⁷ or —C(R⁸)(R⁹)—O-R¹⁰; R² is C₁₋₄ alkyl or C₃₋₈ cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C₁₋₄ alkoxy, or wherein when X is a bond, R² is optionally also CN, CF₃, C₂F₅, C₁₋₄ alkyl or C₃₋₈ cycloalkyl, each of which C₁₋₄ alkyl or C₃₋₈ cycloalkyl is optionally substituted with from 1-3 hydroxy, halogen and C₁₋₄ alkoxy; R³ and R⁴ are selected independently from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₅ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, halogen, CN, or NR⁶R⁷; R⁵ is H, C₁₋₄ alkyl or C3-8 cycloalkyl; R⁶ and R⁷ are each independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₈ alkoxyalkyl, C₃₋₆ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl or heteroaryl(C₁₋₄ alkyl)-; R⁸ and R⁹ are each independently H or C₁₋₄ alkyl, or R⁸ and R⁹ are taken together as ═CH₂, C₂-4 alkenyl, C₂₋₄ alkynyl; and, R¹⁰ is H or C₁₋₄ alkyl. Preferred embodiments of this invention are set forth hereinbelow.

[0014] Said compounds antagonize CRF receptors, that is, they bind to the receptors such that CRF is inhibited from binding to the antagonized receptors. The compounds of this invention are thus useful as therapeutic agents in conditions characterized by excessive CRF expression, and this invention thus provides methods of treating a subject afflicted with a disorder, e.g., an anxiety- or depression-related disorder, characterized by CRF overexpression.

DETAILED DESCRIPTION OF THE INVENTION

[0015] This invention provides a compound of the formula (I):

[0016] wherein the various substituents are as described hereinbelow.

[0017] R¹ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, NR⁶R⁷ or —C(R⁸) (R⁹)—O—R¹⁰. R² is C₁₄ alkyl or C₃₋₈ cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C₁₋₄ alkoxy, or wherein when X is a bond, R² is optionally also CN, CF₃, C₂F₅, C₁₋₄ alkyl or C₃₋₈ cycloalkyl, each of which C₁₋₄ alkyl or C₃₋₈ cycloalkyl is optionally substituted with from 1-3 hydroxy, halogen and C₁₋₄ alkoxy. R³ and R⁴ are each selected independently from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₅ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, halogen, CN, or NR⁶R⁷. R⁵ is H, C₁₋₄ alkyl or C₃₋₈ cycloalkyl. R⁶ and R⁷ are each independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₈ alkoxyalkyl, C₃₋₆ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl or heteroaryl(C₁₋₄ alkyl)-. R⁸ and R⁹ are each independently H or C₁₄ alkyl, or R⁸ and R⁹ are taken together as ═CH₂, C₂₋₄ alkenyl, C₂₋₄ alkynyl. R¹⁰ is H or C₁₄ alkyl. R¹¹ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, phenyl or benzyl, each phenyl or benzyl optionally substituted on the aryl moiety with 1-3 groups of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₄ haloalkoxy, or dimethylamino. R¹², R¹³ and R¹⁴ are each independently H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₆ cycloalkylalkyl or C₁₋₄ haloalkyl.

[0018] X is CHR⁵, NR⁵, O, S, S(O)_(n) or a single bond, wherein n is equal to 0, 1 or 2. D is aryl or heteroaryl attached through an unsaturated carbon atom, wherein said aryl is optionally substituted at any available position with from 1-5 of, and said heteroaryl is optionally substituted with from 1-4 of, A¹, A², A³, A⁴ and A⁵ A¹, A², A³, A⁴ and A⁵ are each independently H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, C₁₋₄ haloalkyl, cyano, nitro, —OR¹², SH, —S(O)_(n)R¹³, —COR¹², —CO₂R —OC(O)R¹³, —NR¹¹COR¹², —N(COR¹²)₂, —N¹¹CONR¹²R¹⁴, or wherein A¹, A², A³, A⁴ and A⁵ are each independently phenyl or phenyl substituted with from 1 to 4 of C₁₋₃ alkyl, C₁₃ alkoxy, halo, cyano, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me or acetyl.

[0019] “Aryl” denotes either the 6-carbon benzene ring or the condensed 6-carbon rings of other aromatic derivatives (see, e.g., Hawley's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., New York (1997)); aryl includes, without limitation, phenyl, napthyl, indanyl and indenyl. “Heteroaryl” rings are aryl rings in which one or more, typically from 1-4, of the ring-member carbon atoms is replace by an atom other than a carbon atom, i.e., a heteroatom (typically O, N or S). Heteroaryl includes, without limitation: pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, indazolyl, thienyl, isoxazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzsothienyl, 2,3-dihydrobenzothienyl-S-oxide, indolinyl, benzoxazolin-2-on-yl and benzodioxolanyl. “Alkyl” means saturated hydrocarbon chains, branched or unbranched, having the specified number of carbon atoms. “Alkenyl” means hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds, which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. “Alkynyl” means hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds, which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. “Alkoxy” means an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Cycloalkyl” means saturated ring groups, including mono-,bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. “Halo” or “halogen” means fluoro, chloro, bromo, and iodo. “Haloalkyl” means both branched and straight-chain alkyls having the specified number of carbon atoms, substituted with 1 or more halogens. “Haloalkoxy” means an alkoxy group substituted by at least one halogen atom. “Substituted” means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto, then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0020] Preferably, R¹ is —C(R⁸)(R⁹)—O—R¹⁰. More preferably, presently, R⁸ is H, R⁹ is C₂H₅ or C₃H₇ and R¹⁰ is C₂H₅. Preferably, R² is unsubstituted C₁₋₄ alkyl; more preferably, presently, R² is C₂H₅. R³ and R⁴ are preferably each H. X is preferably a single bond.

[0021] D is preferably phenyl, more preferably a phenyl group of the formula

[0022] wherein each of A¹, A² and A³ is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen and C₁₋₄ haloalkyl. Even more preferably: A¹ is H, CH₃ or Cl; A is Cl, —OCH₃ or —OCHF₂; and, A³ is H or CH₃. Most preferably, presently, A¹ is C¹ and A³ is H.

[0023] Each of R¹-R¹², X, D and A¹-A⁵ are any of the possible members of the groups listed hereinabove for these substituents. R², for example, being C1-4 alkyl or C3-8 cycloalkyl is each and every one of the members of these groups, i.e., is C1, C2, C3 and C4 alkyl, as well as C3, C4, C5, C6, C7 and C8 cycloalkyl. Moreover, selection of a substituent as a specific member of one of its groups does not limit the choice of the other substituents to less than all of the available selections.

[0024] R¹ is preferably —CR⁸R⁹R¹⁰, and each of R⁸, R⁹ and R10 is preferably H, C1, C2, C3 or C4 alkyl. Moreover, each of the substituents is any one of these five possibilities independently of the identity of the other substituents. Thus, there are at least 125 groups of preferred compounds, each of which is characterized by a different, but preferred, combination of R⁸, R⁹ and R¹⁰ in R¹. These groups of compounds are listed in Tables A and B (hereinbelow). TABLE A R⁸ Alkyl R⁹ H C1 C2 C3 C4 H A1  A2  A3  A4  A5  C1 Alkyl A6  A7  A8  A9  A10 C2 Alkyl A11 A12 A13 A14 A15 C3 Alkyl A16 A17 A18 A19 A20 C4 Alkyl A21 A22 A23 A24 A25

[0025] TABLE B R¹⁰ Alkyl R⁸ + R⁹ H C1 C2 C3 C4 X1  B1  B2  B3  B4  B5  X2  B6  B7  B8  B9  B10 X3  B11 B12 B13 B14 B15 X4  B16 B17 B18 B19 B20 X5  B21 B22 B23 B24 B25 X6  B26 B27 B28 B29 B30 X7  B31 B32 B33 B34 B35 X8  B36 B37 B38 B39 B40 X9  B41 B42 B43 B44 B45 X10 B46 B47 B48 B49 B50 X11 B51 B51 B53 B54 B55 X12 B56 B57 B58 B59 B60 X13 E61 B62 B63 B64 B65 X14 B66 B67 B68 B69 B70 X15 B71 B72 B73 B74 B75 X16 B76 B77 B78 B79 B80 X17 B81 B82 B83 B84 B85 X18 B86 B8  B88 B89 B90 X19 B91 B92 B93 B94 B95 X20 B96 B97 B98 B99  B100 X21  B101  B102  B103  B104  B105 X22  B106  B107  B108  B109  B110 X23  B111  B112  B113  B114  B115 X24  B116  B117  B118  B119  B120 X25  B121  B122  B123  B124  B125

[0026] Table A specifies the identity of the substituent “R⁸” in preferred compounds provided herein; these are listed, in the top row from left to right, as H, and then C1, C2, C3 and C4 alkyl. The identity of the substituent “R⁹” in preferred compounds is also given, along the left side, from top to bottom, as H, and then C1, C2, C3 and C4 alkyl. Thus, each cell of the table identifies a specific combination of R⁸ and R⁹ in a preferred compound. Thus, each cell of the table identifies a specific combination of R⁸ and R⁹ in a preferred compound. Each cell is itself identified by an alphanumeric combination specifying the cell's location within the table.

[0027] Table B specifies the identity of the substituent “R¹⁰” in preferred compounds provided hererein; these are listed, in the top row from left to right, as H, and then C1, C2, C3 and C4 alkyl. Moreover, the R8/R9 combinations set forth in in Table 1 are listed along the left side of the table, from top to bottom, in terms of their cell number from Table A (e.g., “X1” refers to that set of compounds wherein R⁸ and R⁹ are each H). Each cell of Table B thus specifies a specific combination of R⁸, R⁹ and R¹⁰ (e.g., “B1” refers to that set of compounds wherein each of R⁸, R⁹ and R¹⁰ are H)

[0028] R² is preferably C1, C2, C3 or C4 alkyl (each being unsubstituted). Table C hereinbelow lists the combinations of each of these with each of the R⁸/R⁹/R¹⁰ combinations from Table B: TABLE C R¹ ALKYL R⁸/R⁹/R¹⁰ C1 C2 C3 C4 B1 C1 C2 C3 C4 B2 C5 C6 C7 C8 B3 C9 C10 C11 C12 B4 C13 C14 C15 C16 B5 C17 C18 C19 C20 B6 C21 C22 C23 C24 B7 C25 C26 C27 C28 B8 C29 C30 C31 C32 B9 C33 C34 C35 C36 B10 C37 C38 C39 C40 B11 C41 C42 C43 C44 B12 C45 C46 C47 C48 B13 C49 C50 C51 C52 B14 C53 C54 C55 C56 B15 C57 C58 C59 C60 B16 C61 C62 C63 C64 B17 C65 C66 C67 C68 B18 C69 C70 C71 C72 B19 C73 C74 C75 C76 B20 C77 C78 C79 C80 B21 C81 C82 C83 C84 B22 C85 C86 C87 C88 B23 C89 C90 C91 C92 B24 C93 C94 C95 C96 B25 C97 C98 C99 C100 B26 C101 C102 C103 C104 B27 C105 C106 C107 C108 B28 C109 C110 C111 C112 B29 C113 C114 C115 C116 B30 C117 C118 C119 C120 B31 C121 C122 C123 C124 B32 C125 C126 C127 C128 B33 C129 C130 C131 C132 B33 C133 C134 C135 C136 B34 C137 C138 C139 C140 B35 C141 C142 C143 C144 B36 C145 C146 C147 C148 B37 C149 C150 C151 C152 B38 C153 C154 C155 C156 B39 C157 C158 C159 C160 B40 C161 C162 C163 C164 B41 C165 C166 C167 C168 B42 C169 C170 C171 C172 B43 C173 C174 C175 C176 B44 C177 C178 C179 C180 B45 C181 C182 C183 C184 B46 C185 C186 C187 C188 B47 C189 C190 C191 C192 B48 C193 C194 C195 C196 B49 C197 C198 C199 C200 B50 C201 C202 C203 C204 B51 C205 C206 C207 C208 B52 C209 C210 C211 C212 B53 C213 C214 C215 C216 B54 C217 C218 C2190 C220 B55 C221 C222 C223 C224 B56 C225 C226 C227 C228 B57 C229 C230 C231 C232 B58 C233 C234 C235 C236 B59 C237 C238 C239 C240 B60 C241 C242 C243 C244 B61 C245 C246 C2247 C248 B62 C249 C250 C251 C252 B63 C253 C254 C255 C256 B64 C257 C258 C259 C260 B65 C261 C262 C263 C264 B66 C265 C266 C267 C268 B67 C269 C270 C271 C272 B68 C273 C274 C275 C276 B69 C277 C278 C279 C280 B70 C281 C282 C283 C284 B71 C285 C286 C287 C288 B72 C289 C290 C291 C292 B73 C293 C294 C295 C296 B74 C297 C298 C299 C300 B75 C301 C302 C303 C304 B76 C305 C306 C307 C308 B77 C309 C310 C311 C312 B78 C313 C314 C315 C316 B79 C317 C318 C319 C320 B80 C321 C322 C323 C324 B81 C325 C326 C327 C328 B82 C329 C330 C331 C332 B83 C333 C334 C335 C336 B84 C337 C338 C339 C340 B85 C341 C342 C343 C344 B86 C345 C346 C347 C348 B87 C349 C350 C351 C352 B88 C353 C354 C355 C356 B89 C357 C358 C359 C360 B90 C361 C362 C363 C364 B91 C365 C366 C367 C368 B92 C369 C370 C371 C372 B93 C373 C374 C375 C376 B94 C377 C378 C379 C380 B95 C381 C383 C383 C384 B96 C385 C386 C387 C388 B97 C389 C390 C391 C392 B98 C393 C394 C395 C396 B99 C397 C398 C399 C400 B100 C401 C402 C403 C404 B101 C405 C406 C407 C408 B102 C409 C410 C411 C412 B103 C413 C414 C415 C416 B104 C417 C418 C419 C420 B105 C421 C422 C423 C424 B106 C425 C426 C427 C428 B107 C429 C430 C431 C432 B108 C433 C434 C435 C436 B109 C437 C438 C439 C440 B110 C441 C442 C443 C444 B111 C445 C446 C447 C448 B112 C449 C450 C451 C452 B113 C453 454 C455 C456 B114 C457 C458 C459 C460 B115 C461 C462 C463 C464 B116 C465 C466 C467 C468 B117 C469 C470 C471 C472 B118 C473 C474 C475 C476 B119 C477 C478 C479 C480 B120 C481 C482 C483 C484 B121 C485 C486 C487 C488 B122 C489 C490 C491 C492 B123 C493 C494 C495 C496 B124 C497 C498 C499 C500 B125 C501 C502 C503 C504

[0029] Also as described hereinabove, D is most preferably a phenyl substituted with A¹ (presently preferably H or CH₃), A² (preferably Cl, —OCH₃ or —OCHF₂) and A³ (H or CH₃). Tables D and DD hereinbelow identify individual sets of compounds containing each of the possible specific combinations of these groupings. Table D lists combinations of A¹ and A³ (e.g., cell “D1” represents that set of compounds wherein A¹ and A³ are each H); Table DD lists combinations of A¹/A³ with the various presently preferred members of A (e.g., cell “DD1” represents that set of compounds wherein A² is Cl and the A¹/A³ combination is represented by cell “D1” (i.e., A¹ and A³ are each H)): TABLE D A³ A¹ H CH₃ H D1 D2 CH₃ D3 D4

[0030] TABLE DD A² A¹/A³ C1 —OCH₃ —OCHF₂ D1 DD1 DD2 DD3 D2 DD4 DD5 DD6 D3 DD7 DD8 DD9 D4 DD10 DD11 DD12

[0031] Furthermore, as described hereinabove, this invention provides presently preferred compounds comprising combinations of any of the preferred members of R¹ and R² (identified in Table C hereinabove with the designations “C1-C500”) with any of the specific A¹/A²/A³ combinations listed in Table DD; these R¹*R²/A¹*A²*A³ combinations, and hence, individual preferred compounds are listed specifically in Table E hereinbelow. Across the top row of the table, from left to right, are listed individual sets of compounds comprising combinations of the various specific, individual A¹, A² and A³ substituents of the phenyl ring D, as identified by their corresponding cell number in Table DD. The leftmost column of the table lists individual sets of compounds comprising the various specific, individual R¹ and R² substituents, as identified by their corresponding cell number in table C. In this regard, cell number Cl (and hence, compounds in which R¹ is Cl alkyl, R² is —CR⁸R⁹OCR¹⁰, and R⁸, R⁹ and R¹⁰ are each H) corresponds to the individual compounds listed in Table E as E1, E501, E1001, E1501, E2001, E2501, E3001, E3501, E4001, E4501, E5001 and E5501; the other cells of Table C (C2-C500) have a similar correspondence to the individual compounds listed in Table E.

[0032] In addition to the compounds described and listed hereinabove, this invention provides their corresponding pharmaceutically acceptable salt, radiolabelled, various stereoisomeric and prodrug forms. “Pharmaceutically acceptable salts” of compounds of this invention are also provided herein. The phrase “pharmaceutically acceptable” is employed to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0033] “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids.

[0034] Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0035] Pharmaceutically acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0036] Radiolabelled compounds, i.e. wherein one or more of the atoms described are replaced by a radioactive isotope of that atom (e.g. C replaced by ¹⁴C or by ¹¹C, and H replaced by ³H or ¹⁸F), are also provided for herein. Such compounds have a variety of potential uses, e.g. as standards and reagents in determining the ability of a potential pharmaceutical to bind to neurotransmitter proteins, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.

[0037] Each of the stereoisomeric forms of this invention's compounds is also provided for herein. That is, the compounds can have one or more asymmetric centers or planes, and all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Compounds are isolated in either the racemic form, or in the optically pure form, for example, by chiral chromatography or chemical resolution of the racemic form.

[0038] Prodrug forms of this invention's compounds are also provided for herein. Such “prodrugs” are compounds comprising this invention's compounds and moieties covalently bound to the parent compounds such that the portions of the parent compound most likely to be involved with toxicities in subjects to which the prodrugs have been administered are blocked from inducing such effects. However, the prodrugs are also cleaved in the subjects in such a way as to release the parent compound without unduly lessening its therapeutic potential. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol, and amine functional groups in the compounds of Formulae (I-III).

[0039] The compounds provided herein are, for example and without limitation, made by the synthetic routes and schemes set forth hereinbelow.

[0040] Synthesis

[0041] Imidazo[1,2-a]pyrazines (1) of the present invention may be prepared from intermediate compounds of Formula (2) using the procedures outlined in Scheme 1.

[0042] Compounds of Formula (2) (where L=leaving groups such as halogen) may be treated with ammonia or aqueous ammonia in the presence or absence an inert solvent such as alkyl alcohols, at reaction temperatures ranging from −80° C. to 250° C. to give products of Formula (3) (where L is halogen). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methyl-pyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), alkyl esters (preferably EtOAc) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

[0043] The resulting intermediates (3) may then be reacted with alpha haloketone derivatives in a solvent such as aliphatic alcohols or an inert solvent at temperatures ranging from −20° C. to 150° C. to give compounds of Formula (4). Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene).

[0044] The compounds of Formula (4) may be coupled to an aromatic compound of Formula (5) to give a compound of formula (6), with elimination of the leaving group (L). For compound (4), L represents a halide, psuedohalide (such as mesylate, tosylate or triflate), or thiomethyl. For compound (5), L represents groups such as lithium, bromomagnesium, chlorozinc, (dihydroxy) boron, (dialkoxy) boron, trialkylstannyl and the like. The coupling reaction may be performed in the presence of an appropriate catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenyl-phosphine)palladium dichloride, [1,3-bis(diphenylphosphino)propane]nickel dichloride, etc. Two particularly useful methods involve the coupling of chloroheterocycles with in-situ-prepared arylzinc reagents according to the method of Negishi et al. (J. Org. Chem. 1977, 42, 1821), and the coupling with arylboronic esters according to the method of Suzuki et al. (Chem. Letters 1989, 1405). Appropriate solvents for reactions of this type usually include tetrahydrofuran, diethyl ether, dimethoxyethane, dimethylformamide, or dimethylsulfoxide. Typical temperatures range from ambient up to the boiling point of the solvent.

[0045] The compound of formula (6) may be converted to a compound of formula (7) by treatment with phosphorous oxyhalide in dialkylformamide. Compounds of formula (8) may be obtained from a compound of formula (7) by treatment with alkyllithiums, alkylmagnesiumhalides, alkyllithiumcuprates or alkylzinc reagents in an inert solvent such as tetrahydrofuran, diakylether or aromatic hydrocarbons.

[0046] The compound of formula (8) can be converted to a compound of invention (1) by alkylating the alcohol with alkyl halides in the presence of a base in an inert solvent. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride).Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −20° C. to 100° C.

[0047] Alternatively, imidazo[1,2-a]pyrazine (1) of the present invention may be obtained by following the steps outlined in Scheme 2. A compound of Formula (4) may be converted to a compound of Formula (9) by following similar conditions for the conversion of compounds of formula (6) to (7) outlined in Scheme 1. Compound of formula (10) may be obtained from compound (9) by following conditions for the conversion of formula (7) to (8) as shown in Scheme 1. Compound (10) may be alkylated to compound (11) by similar conditions outlined for Formula (8) to (1) outlined in scheme 1. Finally compound of formula (11) can be converted to compound of invention (1) using the condition for the conversion of Formula (4) to (6).

[0048] Alternatively, imidazo[1,2-a]pyrazines of the present invention may be obtained by following the steps outlined in Scheme 3. The compound of Formula (7) may be oxidized to compound of Formula (12) by following well known methods outlined in literature (see: Comprehensive Organic Transformations by R. C. Larock, 1989, pp 604-614).

[0049] The compound of Formula (12) may be subjected to Wittig or Tebbe's reaction conditions to afford compound of Formula (13) which may be reduced to compound of Formula (14).

[0050] The nitrogen containing side chain analogs of imidazo[1,2-a]pyrazine derivatives can be synthesized by following procedures outlined in Scheme 4.

[0051] The compound of the Formula (3) may converted to 3-aminoimidazo[1,2-a}pyrazine derivative of Formula (15) by a three component condensation reaction consisting of primary amine, aldehyde and isonitriles in the presence of an acid in an inert solvent. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid. Also acids include Lewis acids but not limited to aluminum halides, borontrifluoride etherates, LiBF₄, Magnesium halides, tin halides, titanium halides, titanium alkoxides, zinc halides and scandium triflates. Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), haloalkanes or aromatic hydrocarbons (preferably benzene or toluene). The compound of Formula (15) may be converted to the compound of Formula (17) by following similar conditions outlined in Scheme 1.

[0052] Moreover, in addition to compounds made by these routes and schemes, this invention provides pharmaceutical compositions comprising pharmaceutically acceptable carriers and therapeutically effective amounts of the compounds. “Pharmaceutically acceptable carriers” are media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Such media are formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted.

[0053] Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.

[0054] Compounds provided herein are antagonists of receptors for corticotropin releasing factor (“CRF”), a 41 amino acid peptide that is the primary physiological regulator of pro-opiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. Immunohistochemical localization of CRF has also demonstrated that CRF has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

[0055] CRF concentrations have been found to be significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals afflicted with affective disorder or depression [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. Moreover, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)].

[0056] CRF produces anxiogenic effects in animals. Moreover, interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist alpha-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)]. The contents of the above-cited documents are incorporated herein by reference.

[0057] Thus, compounds provided herein which, because of their antagonism of CRF receptors, alleviate the effects of CRF overexpression are expected to be useful in treating these and other disorders. Such treatable disorders include, for example and without limitation: affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis and hypoglycemia.

[0058] This invention thus further provides a method of treating a subject afflicted with a disorder characterized by CRF overexpression, such as those described hereinabove, which comprises administering to the subject a pharmaceutical composition provided herein. Such compositions generally comprise a therapeutically effective amount of a compound provided herein, that is, an amount effective to ameliorate, lessen or inhibit disorders characterized by CRF overexpression. Such amounts typically comprise from about 0.1 to about 1000 mg of the compound per kg of body weight of the subject to which the composition is administered. Therapeutically effective amounts can be administered according to any dosing regimen satisfactory to those of ordinary skill in the art.

[0059] Administration is, for example, by various parenteral means. Pharmaceutical compositions suitable for parenteral administration include various aqueous media such as aqueous dextrose and saline solutions; glycol solutions are also useful carriers, and preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents; also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0060] Alternatively, compositions can be administered orally in solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, stearic acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

[0061] This invention is described in the following examples, which those of ordinary skill in the art will readily understand are not limiting on the invention as defined in the claims which follow thereafter.

EXAMPLES

[0062] Table 1 is a brief summary of compounds provided herein, made according to the synthetic schemes described hereinabove and the examples provided hereinbelow.

[0063] Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on an Varian FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemical ionization (CI) with NH₃ as the carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard 5988A model spectrometer. Melting points were recorded on a Buchi Model 510 melting point apparatus and are uncorrected. Boiling points are uncorrected. All pH determinations during workup were made with indicator paper.

[0064] Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general procedures outlined by D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988). Chromatography (thin layer (TLC) or preparative) was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Otherwise, parts and percentages are by weight. TABLE 1

(Ex.) X Y Z R₁ R₂ mp (° C.)  (1) Cl Cl H Et CH(Me)OH amorph  (2) Cl Cl H Et CH(Me)OMe oil  (3) Cl Cl H Et CH(Me)OEt oil  (4) Cl Cl H Et CH(Et)OH 70-71  (5) Cl Cl H Et CH(Et)OMe oil  (6) Cl Cl H Et CH(Et)OEt oil  (7) Cl Cl H Et CH(n-C₃H₇)OH 159-160  (8) Cl Cl H Et CH(n-C₃H₇)OMe oil  (9) Cl Cl H Et CH(n-C₃H₇)OEt 65-67 (10) Cl Cl H Et CH(C≡CMe)OH 81-82 (11) Cl Cl H Et CH(C≡CMe)OMe oil (12) Cl Cl H Et CH(C≡CMe)OEt oil (13) Cl Cl H Et CH(CPM)OH 131-132 (14) Cl Cl H Et CH(CPM)OEt oil (15) Cl Cl H Et CH(allyl)OEt oil (16) Cl Cl H Et CH(n-Bu)OH oil (17) Cl Cl H Et CH(n-Bu)OEt oil (18) Cl Cl H Et CH[CH(Me)Et]OH amorph. (19) Cl Cl H Et CH[CH(Me)Et]OEt oil (20) Cl Cl H Me CH(n-C₃H₇)OH amorph. (21) Cl Cl H Me CH(n-C₃H₇)OEt 110-111 (22) Cl OMe H Et CH(Et)OH 145-146 (23) Cl OMe H Et CH(Et)OEt oil (24) Cl OMe H Et CH(n-C₃H₇)OH 152-153 (25) Cl OMe H Et CH(n-C₃H₇)OEt oil (26) Cl OCHF₂ H Et CH(Et)OH 144-145 (27) Cl OCHF₂ H Et CH(Et)OC₂H₅ oil (28) Cl OCHF₂ H Et CH(n-C₃H₇)OH 123-124 (29) Cl OCHF₂ H Et CH(n-C₃H₇)OEt 67-68 (30) Me OCHF₂ Me Et CH(n-C₃H₇)OEt 83-84 (31) Me OCHF₂ H Et CH(n-C₃H₇)OH 147-148 (32) Me OCHF₂ H Et CH(n-C₃H₇)OEt oil (33) Cl Cl H Et C(═O)-n-C₃H₇ 95-96 (34) Cl Cl H Et C(═CH₂)-n-C₃H₇ oil (35) H Cl H Et N(Bz)-n-C₃H₇ oil (36) Cl Cl H Et N(Bz)-n-C₃H₇ oil (37) Cl Cl H Et NH(Bz) oil (38) Cl Cl H Et N(Bz)Et oil (39) Cl Cl H Et N(Et)-n-Bu oil (40) Cl Cl H Et N(allyl)Et oil

Example 1

[0065] 8-(2,4-dichlorophenyl)-2-ethyl-3-(1-hyroxyethyl)imidazo[1,2-a]pyrazine

[0066] Part A: Synthesis of 3-amino-2-chloropyrazine:

[0067] (Ref: S. Okada et al Chem. Pharm. Bull. 1971, 19(7), 1344-1357). A mixture of 2,3-dichloropyrazine (20 g, 0.134 moles) and 28% aq. NH₄OH (120 mL) was heated in a resealable pressure tube at 140° C. for 24 h. The solution was cooled and the off-white crystals separated was filtered and dried to afford 16.6 g material (96%, mp 165-166° C.). The crude was quite pure by NMR and used in the next step without purification.

[0068] Part B: Synthesis of 8-chloro-2-ethylimidazo[1,2-a]pyrazine:

[0069] To a solution of 2-amino-3-chloropyrazine (19.5 g, fw=129, 0.15 moles) in dioxane (250.0 mL) was treated with 90% 1-bromo-2-butanone (25 g, fw=151, 1.1 moles, Aldrich) and stirred under nitrogen for 4 h followed by reflux for 48 h. Brick red colored solid separated from the mixture. TLC (1:50 MeOH/CH₂Cl₂) showed a new spot at Rf=0.30 along with disappearance of starting material spot at Rf=0.42. The reaction mixture was cooled to room temperature filtered the solid and washed the solid with diethyl ether (2×100 mL). NMR of the salt in DMS0-D6 revealed a clean product. The salt was dissolved in water (500 mL), adjusted the pH to 8 using solid Na₂CO₃, extracted with EtOAc, washed with brine, dried (MgSO₄) and concentrated in vacuum to afford pale yellow solid. The crude (20 g, 74% yield, mp 73-74° C.) was found to be quite pure by NMR and used without purification in the next step.

[0070] Part C: Synthesis of 8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine:

[0071] A mixture of 8-chloro-2-ethylimidazo[1,2-a]pyrazine (9.05 g, 0.05 mol, fw=181) and 2,4-dichlorobenzeneboronic acid (10.5 g, 0.055 mol, fw=190.81) in toluene (200.0 mL) was treated with 2M aq. Na₂CO₃ (40.0 mL) and EtOH (20.0 mL). The reaction mixture was degassed under vacuum and purged with nitrogen (repeated 3 times) and then added Pd(PPh₃)₂Cl₂ (740 mg, 0.001 mol, fw=738.18, 2 mol %). After the addition the reaction mixture was degassed under vacuum and purged with nitrogen (repeated 3 times). The resultant mixture was refluxed under nitrogen for 24 h. TLC (1:50 MeOH/CH₂Cl₂) showed two new spots at Rf=0.53 and 0.35 along with trace amount of starting material spot at Rf=0.30. The reaction mixture was cooled to room temp and partitioned between 200 ml of 1:1 EtOAc/water. The aq. layer was extracted with EtOAc (2×150 mL), dried (MgSO₄) and concentrated in vacuum to afford yellow oil. The crude (15.1 g, brown yellow solid) was purified by flash column chromatography on a silica gel using 15% EtOAc/hexane to afford the top spot as pale yellow solid (760 mg, mp 71-72° C.) and characterized as 8-(4-chlorophenyl)-2-ethylimidazo[1,2-a]pyrazine. HRMS calcd. for C₁₄H₁₃N₃Cl₁: 258.0798. Found: 258.0788 (M+H). Further elution of the column with 30% EtOAc/hexane gave desired product (bottom spot) as white solid (8.6 g, 59% yield, 125-126° C.). HRMS calcd. for C₁₄H₁₂N₃Cl₂: 292.0408. Found: 292.0409 (M+H).

[0072] Part D: Synthesis of 8-(2,4-dichlorophenyl)-2-ethyl-3-formyl-imidazo[1,2-a]pyrazine:

[0073] POCl₃ (99.6 g, 60.0 mL, 65.0 mmol, fw=153.33) was added dropwise to a cooled (0° C.) stirred solution of dry DMF (200 mL). The resultant mixture was stirred for additional 15 min. and then added 8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazine (14.6 g, 50.0 mmol, fw=292) to the reaction mixture. The reaction mixture was gradually brought to room temperature and stirred for 4 days. The reaction mixture appeared yellow in color. TLC (1:50 MeOH/CH₂Cl₂) revealed absence of starting material spot (Rf=0.35) and showed a new spot at Rf=0.4. The reaction mixture was quenched with ice (750 g), stirred the mixture for 30 min., neutralized with solid sodium carbonate and extracted with EtOAc (3×200 mL), dried (MgSO₄) and concentrated in vacuum to afford yellow solid. The solid was purified by flash column chromatography on a silica gel using 20% EtOAc/hexane to afford 11.7 g (73%, 93-94° C.) of white solid. Anal. calcd. for C₁₅H₁₁Cl₂N₃O: C, 56.27; H, 3.46; N, 13.12. Found: C, 56.13; H, 3.38; N, 12.96.

[0074] Part E: Synthesis of title compound:

[0075] The aldehyde of Part D of Example 1 (0.320 g, 1.0 mmol) was dissolved in anhydrous THF (5.0 mL) and cooled to #78 C under nitrogen. To this mixture was added dropwise 1.4 M MeMgBr in toluene/THF (3.0 mL, 4.2 mmol) and stirred at −78° C. for 3 h. TLC (1:10 MeOH/CH₂Cl₂) revealed absence of starting material spot (Rf=0.88) and showed a new spot at Rf=0.12. The reaction mixture was quenched with satd. NH₄Cl (10.0 mL), stirred the mixture for 10 min., extracted with EtOAc (3×25 mL), dried (MgSO₄) and concentrated in vacuum to afford yellow oil. The residue was purified by flash column chromatography on a silica gel using 2.5% MeOH/CH₂Cl₂ to afford 207 mg (62%) of amorphous wet white solid. HRMS calcd. for C₁₆H₁₆Cl₂N₃O: 336.0670. Found: 336.0678 (M+H).

Example 2

[0076] 8-(2,4-dichlorophenyl)-2-ethyl-3-(lmethoxyethyl)imidazo[1,2-a]pyrazine

[0077] The alcohol from Part E of Example 1 (90.0 mg, 0.268 mmol) was dissolved in dry DMF (2.0 mL) under nitrogen. To this mixture was added 60% NaH (21.4 mg, 0.536 mmol, 2 equiv.) and stirred at room temperature for 30 mins. MeI (excess) was added to the mixture and stirred overnight. TLC (1:10 MeOH/CH₂Cl₂) revealed a new spot (Rf=0.31). The reaction mixture was quenched with water (5.0 mL), stirred the mixture for 10 mins., extracted with EtOAc (3×15 mL), dried (MgSO₄) and concentrated in vacuum to afford yellow oil. The residue was purified by flash column chromatography on a silica gel using 1% MeOH/CH₂Cl₂ to afford yellow oil (32 mg, 34% yield. HRMS calcd. for C₁₇H₁₈Cl₂N₃O: 350.0827. Found:350.0828 (M+H).

[0078] The compounds of examples 3-32 shown in Table 1 were prepared by following the experimental conditions outlined in Examples 1 & 2, hereinabove.

Example 33

[0079] 8-(2,4-dichlorophenyl)-2-ethyl-3-(1-oxo-butyl)imidazo[1,2-a]pyrazine

[0080] Part A: 8-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxybutyl)imidazo[1,2-a]pyrazine:

[0081] The aldehyde (1.6 g, 5.0 mmol, Part D of Example 1) was dissolved in anhydrous THF (25.0 mL) and cooled to −78° C. under nitrogen. To this mixture was added dropwise 2.0 M n-PrMgCl in diethyl ether (6.7 mL, 14.4 mmol) and stirred at −78° C. for 4 h. TLC (1:10 MeOH/CH₂Cl₂) revealed absence of starting material spot (Rf=0.88) and showed a new spot at Rf=0.05. The reaction mixture was quenched with saturated NH₄Cl (30.0 mL), stirred the mixture for 10 min., extracted with EtOAc (3×1O0 mL), dried (MgSO₄) and concentrated in vacuum to afford yellow oil. The residue was purified by flash column chromatography on a silica gel using 2.5% MeOH/CH₂Cl₂ to afford 1.63 g (84%, mp 159-160° C.) of desired product as white solid.

[0082] Part B: Title compound: To a mixture of carbinol (1.1 g, 0.003 moles, fw364, Part A of Example 33) in toluene (25 mL) was added MnO₂ and refluxed under nitrogen for 24 h. TLC (1:10 MeOH/CH₂Cl₂) revealed absence of starting material spot (Rf=0.5) and showed a new spot at Rf=0.86. The reaction mixture was cooled to room temperature, filtered through celite, washed the celite with EtOAc (3×50 mL), and concentrated in vacuum to afford yellow oil. The residue was purified by flash column chromatography on a silica gel using 1% MeOH/CH₂Cl₂ to afford 580 mg (53%, mp 95-96° C.) of white solid.

Example 34

[0083] 8-(2,4-dichlorophenyl)-2-ethyl-3-(1-propylvinyl)imidazo[1,2-a]pyrazine

[0084] To a solution of keto imidazopyrazine (181 mg, 0.5 mmol, Part B of Example 33) in THF (5.0 mL) at room temp was added 0.5 M toluene solution of the Tebbe reagent (1.2 mL, 0.6 mmol) dropwise under nitrogen atmosphere. The reaction mixture was slightly exothermic during addition and continued stirring for 1 h. TLC (3:7 EtOAc/hexane) revealed absence of starting material (Rf=0.5) along with a new spot (Rf=0.46). The reaction mixture was diluted with 15 mL of Et₂O and then added 3-5 drops of 1.0 N Aq. NaOH. After gas evolution ceases, the mixture was filtered through celite, evaporated to dryness and purified by flash column chromatography on a silica gel using 10% EtOAc/hexane to afford yellow oil (81 mg, 45%). HRMS calcd. for C₁₉H₂₀N₃Cl₂: 360.1034. Found:360.1033

[0085] The compound of example 35 was prepared according to the experimental conditions outlined in Examples 33 and 34, hereinabove

Example 36

[0086] 8-(2,4-dichlorophenyl)-2-ethyl-3-(N-propylbenzylamino) imidazo[1,2-a]pyrazine

[0087] Part A: 3-benzylamino-8-chloro-2-ethylimidazo[1,2-a]pyrazine:

[0088] To a solution of 2-amino-3-chloropyrazine (1.3 g, fw=129, 10.0 mmole) in MeOH (50.0 mL) was treated with propionaldehyde (0.58 g, fw=58, 10.0 mmole, Aldrich), AcOH (1.2 g, 20 mmol, fw=60) and benzyl isocyanide (STENCH, 1.17 g, 10.0 mmol, fw=117.15, Aldrich). The resultant suspension was stirred at room temp overnight. TLC (1:50 MeOH/CH₂Cl₂) showed a new spot at Rf=0.24 along with unreacted starting material spot at Rf=0.42. The unreacted isocyanide was destroyed by acidifying the reaction mixture to pH 1 using 1N HCl. After acidification the reaction mixture was stirred at room temp for 30 mins, evaporated to dryness, residue dissolved in water, adjusted the pH to 8 using KHCO₃, extracted the reaction mixture with EtOAc (3×50 mL) and dried with anhydrous MgSO₄. The solvent was evaporated from the reaction mixture and the residue (pale yellow solid) was partitioned between 50 ml of 1:1 EtOAc/aq. NaHCO₃. The aq. layer was extracted with EtOAc (2×15 mL), dried (MgSO₄) and concentrated in vacuum to afford pale yellow solid (3.0 g). The crude was treated with CH₂Cl₂ and filtered the white solid (0.75 recovered starting material). The filtrate was evaporated and purified by flash column chromatography on a silica gel using 30% EtOAc/hexane to afford 0.42 g (34% yield) desired product as yellow oil.

[0089] Part B: N-Alkylation: A mixture of 3-benzyamino-8-chloro-2-ethylpyrazine (415 mg, 0.00145 moles, fw=286.45) in DMF (2.0 mL) was treated with 60% NaH (70 mg, 0.00174 moles, 1.2 equiv.) at room temp under nitrogen atmosphere and stirred for 15 mins. To this mixture was added 1-iodopropane (0.296 g, 0.00174 moles, 1.2 equiv.) and stirred at room temp for 4 h. TLC (1:50 MeOH/CH₂Cl₂) showed a new spot at Rf=0.33 along with several minor spots below the product. Since the starting material spot overlapped with one of the minor spots, the reaction was allowed to continue over weekend. The solvent from the reaction mixture was evaporated under vacuum, quenched with water, extracted with EtOAc (3×10 mL), dried with MgSO₄. The solvent from the reaction mixture was evaporated and the crude was purified by flash column chromatography on a silica gel using 15% EtOAc/hexane to afford the desired product as yellow oil (170 mg, 35% yield). HRMS calcd. for C₁₈H₂₂N₄Cl₁:329.1533. Found: 329.1530 (M+H).

[0090] Part C: Suzuki reaction: A mixture of above chloro compound (0.140 g, 0.43 mmol, fw=328), 2,4-dichlorobenzeneboronic acid (95 mg, 0.65 mmol, fw=190.81) in toluene (5.0 mL) was treated with 2M aq. Na₂CO₃ (2.0 mL) and EtOH (1 mL). The reaction mixture was degassed under vacuum and purged with nitrogen (repeated 3 times) and then added Pd(PPh₃)₂Cl₂ (18. 5 mg, 0.005 mmol, fw=738.18). After the addition the reaction mixture was degassed under vacuum and purged with nitrogen (repeated 3 times). The resultant mixture was refluxed under nitrogen for 6 h. TLC (1:50 MeOH/CH₂Cl₂) showed two new spots at Rf=0.75 and 0.5 along with small amount of starting material spot at Rf=0.33. The reaction mixture was cooled to room temp and partitioned between 20 ml of 1:1 EtOAc/water. The aq. layer was extracted with EtOAc (2×15 mL), dried (MgSO₄) and concentrated in vacuum to afford yellow oil. The crude was purified by flash column chromatography on a silica gel using 10% EtOAc/hexane to afford the top spot as yellow solid (20 mg). Further elution of the column with 15% EtOAc/hexane gave desired product (bottom spot) as yellow oil (60 mg, 40% yield, 125-126° C.). Also recovered 27.5 mg of unreacted chloropyrazine derivative. Top spot was characterized as mono chloro derivative of Example 35. HRMS calcd. for C₂₄H₂₆N₄Cl₁:405.1846. Found: 405.1841 (M+H). Bottom spot desired product. HRMS calcd. for C₂₄H₂₅N₄Cl₂: 439.1456. Found: 439.1455 (M+H).

[0091] The compounds of examples 37 to 40 were prepared by following experimental conditions outlined in Example 36, hereinabove. 

What is claimed is:
 1. A method of treating a subject afflicted with irritable bowel syndrome comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula I:

wherein: X is CHR⁵, NR⁵, O, S, S(O)_(n) or a single bond, wherein n is equal to 0, 1 or 2; D is aryl or heteroaryl attached through an unsaturated carbon atom and wherein said aryl or heteroaryl is optionally substituted at any available position with from 1-5 of A¹, A², A³, A⁴ and A⁵; A¹, A², A³, A⁴ and A⁵ are each independently H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halo, C₁₋₄ haloalkyl, cyano, nitro, —OR¹², SH, —S(O)_(n)R¹³, —COR¹², —CO₂R¹², —OC(O)R¹³, —NR¹¹COR¹², —N(COR¹²)², —NR¹¹CONR¹²R¹⁴, or wherein A¹, A², A³, A⁴ and A⁵ are each independently phenyl or phenyl substituted with from 1 to 4 of C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, cyano, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me or acetyl; R¹ is C₁₋₁₀ alkyl, C₂-10 alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, NR⁶R⁷ or —C(R⁸) (R⁹)—O—R¹⁰; R² is C₁₋₄ alkyl or C₃₋₈ cycloalkyl, each of which is optionally substituted with from 1-3 hydroxy, halogen or C₁₋₄ alkoxy, or wherein when X is a bond, R² is CN, CF₃, or C₂F₅; R³ and R⁴ are independently H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₅ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, halogen, CN, or NR⁶R⁷; R⁵ is H, C₁₋₄ alkyl or C₃₋₈ cycloalkyl; R⁶ and R⁷ are each independently H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₈ alkoxyalkyl, C₃₋₆ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, aryl, aryl(C₁₋₄ alkyl)-, heteroaryl or heteroaryl(C₁₋₄ alkyl)-; R⁸ and R⁹ are each independently H or C₁₋₄ alkyl, or R⁸ and R⁹ are taken together as ═CH₂; R¹⁰ is H or C1-4 alkyl; R¹¹ is H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, phenyl or benzyl, each phenyl or benzyl optionally substituted on the aryl moiety with 1-3 groups of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, or dimethylamino; and, R¹², R¹³ and R¹⁴ are each independently H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₆ cycloalkylalkyl or C₁₋₄ haloalkyl.
 2. The method of claim 1, wherein X is a single bond.
 3. The method of claim 1, wherein D is phenyl.
 4. The method of claim 3, wherein the phenyl is

and wherein each of A¹, A² and A³ is independently H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, C₁₋₄ haloalkyl or OR¹².
 5. The method of claim 4, wherein A¹ is H, CH₃ or Cl.
 6. The method of claim 4, wherein A² is Cl, —OCH₃ or —OCHF₂.
 7. The method of claim 4, wherein A³ is H or CH₃.
 8. The method of claim 4, wherein: A¹ is H, CH₃ or Cl; A² is Cl, —OCH₃ or —OCHF₂ and A³ is H or CH₃.
 9. The method of claim 1, wherein R¹ is —C(R⁸)(R⁹)—O—R¹⁰.
 10. The method of claim 9, wherein each of R⁸, R⁹ and R¹⁰ are independently H or C₁₋₄ alkyl.
 11. The method of claim 10, wherein R⁸ is H.
 12. The method of claim 10, wherein R⁹ is C₂H₅ or C₃H₇.
 13. The method of claim 12, wherein R¹⁰ is H.
 14. The method of claim 10, wherein R⁸ is H, R⁹ is C₂H₅ or C₃H₇ and R¹⁰ is H.
 15. The method of claim 1, wherein R² is unsubstituted C1-4 alkyl.
 16. The method of claim 15, wherein R¹ is C₂H₅.
 17. The method of claim 1, wherein each of R³ and R⁴ are H
 18. The method of claim 1, wherein R¹ is —C(R⁸)(R⁹)—O—R¹⁰, R is unsubstituted C₁₋₄ alkyl, each of R³ and R⁴ is H, X is a single bond and D is phenyl of the formula

wherein R⁸ is H, R⁹ is C₂H₅ or C₃H₇, R¹⁰ is H, each of Al, is H, A² is Cl, —OCH₃ or —OCHF₂ and A³ is H. 